Macromolecules 2007, 40, 4859-4864
4859
Cyclic Poly(thioglycolide) and Poly(D,L-thiolactide) by Zwitterionic Polymerization of Dithiolane-2,4-diones Hans R. Kricheldorf,* Nino Lomadze, and Gert Schwarz Institut fu¨r Technische und Makromolekulare Chemie, UniVersita¨t Hamburg, Bundesstrsse 45, D-20146 Hamburg, Germany ReceiVed March 6, 2007; ReVised Manuscript ReceiVed May 7, 2007 ABSTRACT: Dithiolane-2,4-dione was polymerized either by heating in bulk to 140 °C or by reacting at 20 °C using pyridine and triethylamine as catalysts. Whereas the thermal polymerization almost exclusively yielded cyclic poly(thioglycolide), the samples prepared at 20 °C by means of tertiary amines contained cyclic and linear chains. The end groups of the linear chains varied with the nonsolvent used for the workup procedure, because chains having reactive end groups were immobilized by rapid crystallization and reacted at the electrophilic CO-chain end with the nonsolvent. D,L-5-Methyldithiolane-2,4-dione proved so stable that tertiary amines did not catalyze its polymerization even at 100 °C. Thermal polymerization at 160 °C yielded oligoester mainly consisting of cyles. A zwitterionic polymerization mechanism allowing for simultaneous chain-growth and stepgrowth polymerization is discussed.
Introduction In contrast to normal aliphatic polyesters, aliphatic polythioesters have not attracted much interest in previous decades. However, the recent discovery of Steinbu¨chel and Lu¨keEversloh1-3 that certain microorganisms can produce homo- and copolyesters of β-mercapto carboxylic acids will certainly stimulate further research activities in this field. Since the enzymatic capabilities of microbes are limited to polycondensations of β-mercapto carboxylic acids, the polyesters of R-mercapto carboxylic acids (which are the thio analogs of polyglycolide and polylactide) need to be prepared by chemical methods. Low molar mass poly(thioglycolide) was first prepared by Scho¨berl4-7 via polycondensation of mercapto acetic acid and its methyl ester or by ring-opening polymerization (ROP) of the cyclic dimer (i.e., 1,4-dithiane-2,5-dione). Low molar mass poly(thioglycolide) and poly(thiolactide) were also prepared by ROP of oxathiolane 2,4-diones.8,9 Synthesis and polymerization of dithiolane-2,4-dione were first described by Kricheldorf and Schwarz10,11 about 30 years ago. It was found that tertiary amines were the only useful catalysts, and in extremely pure dioxane high molar mass poly(thioglycolide) was obtained (eq 1). Unfortunately, this polymer
These polymerizations are of particular interest for two reasons. First, they yield cyclic polypeptides which are difficult to prepare by other synthetic methods. Second, the polymerizations combine both chain-growth and step-growth polymerizations (eqs 4 and 5) although both chain-growth reactions are usually treated in text books as two quite different and incompatible polymerization processes. In this connection the present work had the purpose to reinvestigate thermal and pyridine-catalyzed polymerizations of dithiolane-2,4-diones by MALDI-TOF mass spectrometry to find out if these polymerization methods generate cyclic polythioesters. A positive result will have the consequence that polymerizations involving simultaneous chaingrowth and step-growth reactions will represent a concept of broader validity and not just a curiosity of R-amino acid NCAs. In this context, it should be mentioned that zwitterionic polymerizations were studied by several research groups,14-36 but in all publications which appeared before 2006 the formation of cyclic polymers was neither postulated nor war the detection of cyclic polymers in complex reaction mixtures feasible before MALDI-TOF mass spectrometer was available. Only one quite recent paper36 which appeared just when this work was submitted for publication reported on the formation of cyclic polymers (i.e., poly-L-lactides) by zwitterionic polymerization. Experimental Section
is a highly crystalline material for which only two inert solvents were found, namely dichloroacetic acid and hexafluoroacetone sesquihydrate.8 Since 30 years ago neither deuterated dichloroacetic acid nor 13C NMR spectroscopy or MALDI-TOF mass spectrometry was available, it was difficult to identify end groups and to elaborate a polymerization mechanism. Quite recently it was found12 that pyridine-catalyzed polymerizations of R-amino acid N-carboxy anhydrides (NCAs) including Sar-NCA yield cyclic polypeptides via a zwitterionic polymerization mechanism (eqs 2-5). Similar results were found for “spontaneous” polymerizations of NCAs in nucleophilic polar solvents, such as N-methylpyrrolidone or DMSO13 which also play the role of catalysts in analogy to pyridine.
Materials. Carbon disulfide, chloroacetic acid, and 2-bromoacetic acid were purchased from ACROS Organics (Geel, Belgium) and used as received. Pyridine and triethylamine (ACROS Org.) were distilled over powdered calcium hydride. Dry DMSO was purchased from Aldrich Co. (Milwaukee, WI). N-Methylpyrrolidone was distilled over P4O10 in vacuo. Pyridine was distilled over freshly powdered calcium hydride, and dioxane was distilled over sodium. Dithiolane-2,4-dione (DTD). This monomer was prepared from xanthogen acetic acid and thionyl chloride in refluxing chloroform as described previously.1 It was twice distilled in a vacuum of 10-2 mbar. A yellowish crystalline product with mp 45-46 °C was obtained. D,L-5-Methyl Dithiolane-2,4-dione (MDTD). A. 2-Xanthogen Proprionic Acid. Sodium (1.0 mol) was dissolved in dry ethanol (450 mL) and carbon disulfide (1.1 mol) was added rapidly but dropwise under cooling with ice. This solution was stored for 48 h at 20-25 °C under an atmosphere of nitrogen. A 5 M aqueous
10.1021/ma0705467 CCC: $37.00 © 2007 American Chemical Society Published on Web 06/16/2007
4860
Kricheldorf et al.
solution of KOH (50 mL) was then added at once, and under cooling with ice, 2-chloropropionic acid (0.25 mol) was added dropwise. Addition of aqueous KOH and 2-chloropropionic acid was repeated three times. After 20 h of stirring at 20-25 °C, water (60 mL) was added and the ethanol was completely distilled off in vacuo by means of a rotating evaporator. The remaining alkaline solution was cooled with ice and acidified by dropwise addition of precooled concentrated hydrochloric acid (120 mL). The oily product was extracted with three 300 mL portions of ethyl acetate. The combined extracts were washed with water (twice), dried over Na2SO4, and concentrated in vacuo. B. Silylation of 2-xanthogen Propionic Acid. The crude product was dissolved in dry tetrahydrofuran (1.2 L), chlorotrimethylsilane (1.0 mol) was added, and a mixture of triethylamine (1.0 mol) and tetrahydrofuran (100 mL) was added rapidly but dropwise. The reaction mixture was refluxed for 2 h, cooled with ice, and filtered under exclusion of moisture (the triethylamine hydrochloride was washed with ligroin). The combined filtrates were concentrated in vacuo and filtered again. Finally, the liquid product was distilled over a short-path apparatus in a vacuum of 10-2 mbar at a bath temperature of 60-65 °C. Yield (relative to 2-chloropropionic acid): 73%. 1H NMR (CDCl /TMS): δ ) 0.29 (s, 9H), 1.40 (t, 3H), 1.50 3 (d, 3H), 4.30 (q, 1H) 4.60 (q, 2H) ppm. C. Cyclization. The silylated 2-xanthogen propionic acid (0.5 mol) was dissolved in dry chloroform (250 mL), and thionyl chloride (0.75 mol) was added. This mixture was stirred for 20 h at 20-25 °C and afterward refluxed for 2 h. After evaporation of the chloroform, dry chloroform was added to the residue and evaporated again to remove most of the SOCl2. The residue was then dissolved in ethylacetate (200 mL), cooled with ice and washed with 300 mL portions of cold 5% aqueous NaCO3H and cold water (twice). The CH2Cl2 solution was dried over CaCl2 and concentrated. The crude product was distilled over short-path apparatus at a bath temperature of 60-70 °C in a vacuum of 10-1 mbar. Three fractions were taken, and the middle fraction (yield: 41%) was found to be sufficiently pure on the basis of its 400 MHz 1H NMR spectrum. n22 D ) 1.5725. Anal. Calcd. for C4H4O2S2 (116.09): C, 32.42; H, 2.72; S, 43.27. Found: C, 32.52; H, 2.84; S, 42.72. 1H NMR (CDCl /TMS): δ ) 1.77 (d, 3H), 4.77 (q, 1H). 3 13C NMR (CDCl /TMS): δ ) 19.07, 58.55, 186.96, 199.45 ppm. 3 Polymerizations of DTD. (1) Thermal Polymerization. DTD (20 mmol) was heated in a 20 mL glass flask having silanized glass walls to a temperature of 140 °C for 20 h, whereby the product solidified. This reaction product was characterized by MALDITOF mass spectroscopy without any purification or fractionation. An analogous polymerization was conducted at 120 °C for 48 h. (2) Pyridine-Catalyzed Polymerizations. DTD (20 mmol) was dissolved in dry pyridine and stored at 20 °C for 24 h. Evolution of gas and precipitation of crystalline poly(thioglycolide) began within the first hour. This experiment was repeated three times and the reaction mixtures were worked up in four ways: (a) the reaction mixture was diluted with pyridine (10 mL) and filtered under an atmosphere of dry nitrogen. The wet polythioester was transferred into a test tube and immersed for 15 min in an oil bath preheated to 160 °C. After cooling with ice, the crude product was characterized. (b) The reaction mixture was poured into water (100 mL) and the polythioester was isolated by filtration. (c) The reaction mixture was poured into methanol (100 mL). (d) The reaction mixture was poured into dry ethanol (100 mL). (3) Triethylamine-Catalyzed Polymerization. DTD (20 mmol) was dissolved in dry dioxane (10 mL), and triethylamine (2 mmol) was injected. After 48 h at 20 °C, the reaction mixture was poured: (a) into water (100 mL), (b) into methanol (100 mL), or (c) into ethanol (100 mL). After isolation by filtration, the polythioester was dried in vacuo at 60 °C. Polymerization of MDTD. (1) Thermal Polymerization. MDTD (20 mmol) was heated in a 20 mL glass flask having
Macromolecules, Vol. 40, No. 14, 2007 Table 1. Calculated Masses (Including K+ Doping) of Polythioesters Resulting from Polymerizations of DTD and MDTDa DP
C (DTD)
La
Lb
Lc
C (MDTD)
10 11 12 13 14 15 16 17 18 19 20 25
780.0 854.1 928.2 1002.3 1076.4 1150.5 1224.6 1298.6 1372.8 1447.0 1521.1 1891.6
798.0 872.1 946.2 1020.3 1094.4 1168.5 1242.6 1316.6 1390.9 1465.0 1539.0 1909.6
812.0 886.1 960.2 1034.3 1108.4 1182.5 1256.6 1330.7 1405.0 1479.0 1554.0 1923.6
826.0 900.1 974.2 1048.3 1122.4 1196.5 1270.6 1344.7 1419.0 1493.0 1568.0 1937.6
920.3 1008.4 1096.6 1184.7 1272.9 1361.0 1449.1 1537.3 1625.4 1713.5 1801.6 2242.2
a These masses were calculated for DPs between 10 and 25, because this mass range was preferentially measured (or limited by the MALDI method); see Figures 1-3.
silanized glass walls to 160 °C for 24 h. Thereby, a viscous melt was obtained, the 1H NMR spectrum of which indicated complete conversion: 1H NMR (CDCl3/TMS), δ ) 1.54 (d, 3H), 4.38 (s, broad), 1H) ppm. (2) 4-Dimethylaminopyridine-Catalyzed Polymerization. MDTD (20 mmol) and 4-N,N-dimethylaminopyridine (20 mmol) were mixed in a 20 mL glass flask and thermostated at 60 °C for 24 h, but no polymerization occurred. After the reaction was heated to 100 °C for 24 h, a black tar was obtained. (3) Parallel Experiment. In a parallel experiment, the polythioester was dissolved in CH2Cl2 (15 mL) and precipitated into methanol. Measurements. The inherent viscosities were measured in dichloroacetic acid with an automated Ubbelohde viscometer thermostated at 30 °C. The 400 MHz 1H NMR spectra were recorded on a Bruker “Advance 400” in 5 mm o.d. sample tubes. Dichloroacetic acid containing TMS (1 vol %) and C6D6 (10 vol %) served as solvent for polythioglycolide. All other 1H NMR spectra were measured in CDCl3. The IR spectra were recorded on a Nicolet FT spectrometer Md “Impact” 410” between NaCl prisms. The MALDI-TOF mass spectra were measured with a Bruker Biflex III mass spectrometer equipped with a nitrogen laser (λ ) 337 nm). All spectra were recorded in the reflection mode using an acceleration voltage of 20 kV. The irradiation targets were prepared with dithranol as matrix and potassium trifluoroacetate as dopant. Chloroform served as solvent for poly(D,L-thiolactate) and dichloroacetic acid for poly(thioglycolide). The masses calculated for the reaction products are summarized in Table 1.
Results and Discussion Thermal Polymerization of Dithiolane-2,4-dione (DTD). In two previous publications1,2 it was demonstrated that tertiary amines are excellent catalysts for the ring-opening polymerizations of DTD even at temperatures below 20 °C. For a proper understanding of the results obtained with tertiary amines as catalysts, it seemed to be advisable to discuss at first the outcome of thermal polymerizations. From preliminary experiments (not described here in detail) it was learned that temperatures g120 °C are needed for complete polymerization of DTD within 24 or 48 h. At temperatures
